早期乳腺癌內(nèi)分泌治療的一些進(jìn)展水

1、會(huì)計(jì)學(xué)1早期乳腺癌內(nèi)分泌治療的一些進(jìn)展水早期乳腺癌內(nèi)分泌治療的一些進(jìn)展水HER2/neu基因過表達(dá)基因過表達(dá)HER2低表達(dá)低表達(dá)HER2過表達(dá)過表達(dá)內(nèi)分泌應(yīng)答內(nèi)分泌應(yīng)答高應(yīng)答高應(yīng)答應(yīng)答不完全應(yīng)答不完全無應(yīng)答無應(yīng)答高應(yīng)答高應(yīng)答應(yīng)答不完全應(yīng)答不完全無應(yīng)答無應(yīng)答絕經(jīng)狀況絕經(jīng)狀況前前后后前前后后前和后前和后前前后后前前后后前和后前和后低低危危淋巴結(jié)陰性且具有以下所有淋巴結(jié)陰性且具有以下所有特征：特征：pTpT2cm2cm, Grade 1，無血管侵襲，無血管侵襲，HER2(-)，ER和和/或或PR表達(dá)，年齡表達(dá)，年齡35歲歲EEE EE E中中危危淋巴結(jié)陰性且至少具有以下淋巴結(jié)陰性且至少具有以下一個(gè)特

2、征：一個(gè)特征：pT 2cm, Grade 2-3，血管侵襲，血管侵襲，HER2(-)，ER和和/或或PR陰性，年齡陰性，年齡4個(gè)淋巴結(jié)陽性個(gè)淋巴結(jié)陽性CECEC CE EC CE ECCE+TrCE+TrCE+TrCE+TrC+TrEBCTCG. Lancet 2005EBCTCG. Lancet 2005復(fù)發(fā)率復(fù)發(fā)率(%)(%)復(fù)發(fā)復(fù)發(fā)時(shí)間（年）時(shí)間（年）乳腺癌死亡率乳腺癌死亡率60601515年受益率年受益率11.8% (SE 1.3)11.8% (SE 1.3)時(shí)序檢驗(yàn)時(shí)序檢驗(yàn)2p0.000012p0.00001乳腺癌死乳腺癌死亡率亡率(%)(%)50504040303020201010

3、0 0服用他莫服用他莫昔芬約昔芬約5 5年年25.6%25.6%安慰劑安慰劑34.8%34.8%0 05 510101515時(shí)間（年）時(shí)間（年）11.911.925.725.78.38.317.817.86060505040403030202010100 01515年獲益年獲益 11.8% (SE 1.3)11.8% (SE 1.3)時(shí)序檢驗(yàn)時(shí)序檢驗(yàn) 2p0.000012p0.00001服用服用他莫昔他莫昔芬芬約約5 5年年33.2%33.2%安慰劑安慰劑45.0%45.0%0 05 51010151526.526.538.338.315.115.124.724.7SE, SE, 為標(biāo)準(zhǔn)誤差為

4、標(biāo)準(zhǔn)誤差芳香化酶抑制劑芳香化酶抑制劑他莫昔芬先治療他莫昔芬先治療2 23 3年年初始輔助治初始輔助治療試驗(yàn)療試驗(yàn)換藥治療試驗(yàn)換藥治療試驗(yàn)延續(xù)輔助治延續(xù)輔助治療試驗(yàn)療試驗(yàn)他莫昔芬他莫昔芬芳香化酶抑制劑芳香化酶抑制劑他莫昔芬他莫昔芬芳香化酶抑制劑芳香化酶抑制劑他莫昔芬他莫昔芬初始和序貫治初始和序貫治療試驗(yàn)療試驗(yàn)他莫昔芬他莫昔芬他莫昔芬他莫昔芬芳香化酶抑制劑芳香化酶抑制劑芳香化酶抑制劑芳香化酶抑制劑0 05 5時(shí)間（年）時(shí)間（年）芳香化酶抑制劑芳香化酶抑制劑隨機(jī)分組隨機(jī)分組安慰劑安慰劑他莫昔芬先治療他莫昔芬先治療5 5年年隨機(jī)分組隨機(jī)分組隨機(jī)分組隨機(jī)分組隨機(jī)分組隨機(jī)分組Smith IE. SABCS

5、, 2007Coombes et al. J Clin Oncol. 2006;24(18S):933s. Abstract LBA527The Intergroup Exemestane Study (IES) group. Lancet. 2007 Feb 17;369(9561):559-70.n有過半的委員也支持對(duì)于接受有過半的委員也支持對(duì)于接受SSRISSRI類抗抑郁藥類抗抑郁藥的病人起始使用的病人起始使用AIsAIs1. Fisher B, et al. J Natl Cancer Inst. 2001;93:684-690. 2. Peto R, et al. SABCS 200

6、7. Abstract 48.Tamoxifen treatment for 5 additional yearsPatients with breast cancer treated with adjuvant tamoxifen for 5 years(N = 11,500)No additional TamoxifenYear 10Year 5Peto R, et al. SABCS 2007. Abstract 48.Annual assessments included compliance, hospital admissions, breast cancer recurrence

7、 (or new contralateral disease), other new primary cancer, and death.Peto R, et al. SABCS 2007. Abstract 48.ParameterAnnual Event Rate, % of Patients Ratio of Rates With Continued vs Stopped Tamoxifen (SE)Continued TAMStopped TAMAll recurrences/yr2.93.40.866 (0.048*) Years 0-13.23.60.89 (0.07) Years

8、 2-42.83.30.87 (0.08) Years 5+2.43.00.77 (0.12)Deaths1.41.50.895 (0.070) Years 0-11.01.01.00 (0.14) Years 2-41.61.80.90 (0.10) Years 5+1.92.40.79 (0.13)P = .0051. Howell A, et al. Lancet. 2005;365:60-62.2. Forbes JF M, et al. SABCS 2007. Abstract 41.Postmenopausal women with early-stage invasive bre

9、ast cancer(N = 6241)Anastrozole(n = 3125)Tamoxifen(n = 3116)Long-termfollow-upYear 5Outcome (Hormone ReceptorPositive Patients)HR (95% CI)P ValueDFS0.85 (0.76-0.94).003TTR0.76 (0.67-0.87).0001TTDR0.84 (0.72-0.97).022CLBC0.60 (0.42-0.85).004OS0.97 (0.86-1.11).70Death after recurrence0.90 (0.75-1.07).

10、20Forbes JF, et al. SABCS 2007. Abstract 41.Long-term results showed that anastrozole superior to tamoxifen for DFS, TTR, TTDR, and CLBC, but not for OS and deaths after recurrence Similar findings observed when analyses restricted to hormone receptorpositive populationForbes JF, et al. SABCS 2007.

11、Abstract 41.Serious Adverse Events, n (%)On TreatmentOff TreatmentAnastrozole(n = 3092)Tamoxifen(n = 3094)Anastrozole(n = 3092)Tamoxifen(n = 3094)Fracture episodes*375 (12.13)234 (7.56)146 (4.72)143 (4.62)Treatment-related events153 (4.95)284 (9.18)49 (1.58)57 (1.84)Myocardial infarction34 (1.10)33

12、(1.07)26 (0.84)28 (0.90)Cerebrovascular accident20 (0.65)34 (1.10)22 (0.71)20 (0.65)Endometrial cancer4 (0.13)12 (0.39)1 (0.03)12 (0.34)Excess in fractures diminished after cessation of therapy RR of fracture for anastrozole vs tamoxifen for Years 0-5: 1.55 (P 1 fracture episode allowed1. Brufsky A,

13、 et al. J Clin Oncol. 2007;25:829-836.2. Brufsky A, et al. SABCS 2007. Abstract 27.Brufsky A, et al. SABCS 2007. Abstract 27.Postmenopausal women with ER-positive or PgR-positive breast cancer(N = 602)*All patients treated with calcium and vitamin D.ZA initiated when T-score decreased to -2 or clini

14、cal fracture occurs.Delayed ZA*+Letrozole 2.5 mg/day(n = 301)Upfront ZA*4 mg IV every 6 months+Letrozole 2.5 mg/day(n = 301)Brufsky A, et al. SABCS 2007. Abstract 27.-4-3-2-101234Lumbar Spine BMDTotal Hip BMDChange in BMD at 36 Mos (%)P .0001P .0001Upfront ZADelayed ZASingh S, et al. SABCS 2007. Abs

15、tract 28.*Preliminary results for patients who completed first year of treatment; final N will be 1000.T-scores at lumbar spine or femoral neck.Observation(n = 227 112 anastrozole) Postmenopausal women at high risk for breast cancer(N = 350*)Stratum I (Normal)T-score -1(n = 227)Stratum II(Osteopenic

16、) -2.5 T-score -1(n = 80)Stratum III(Osteoporotic)-4 T-score 6 monthsEllis G, et al. SABCS 2007. Abstract 47.Gnant M, et al. ASCO 2008. Abstract LBA4.Accrual 1999-20061803 premenopausal breast cancer patientsEndocrine-responsive (ER and/or PgR positive)Stage I and II, 10 positive nodesNo chemotherap

17、y except neoadjuvantTreatment duration: 3 yrsTamoxifen20 mg/dayAnastrozole 1 mg/dayTamoxifen 20 mg/day +Zoledronic acid 4 mg Q6MosAnastrozole 1 mg/day +Zoledronic acid 4 mg Q6MosSurgery (+RT)Goserelin 3.6 mg Q28DGnant M, et al. ASCO 2008. Abstract LBA4.Synergy withanticancer drugsInduces tumorcell a

18、poptosisStimulates immunesurveillanceInhibits angiogenesisDecreases matrix invasionPrimary tumorAngiogenesisInvasionArrest in distant capillaryMetastasesAdhesion andextravasationMicrometastasesDecreases adhesion to boneGnant M, et al. ASCO 2008. Abstract LBA4.Time Since Randomization (Mos)No. at Ris

19、kNo ZAZA8999048388517447355655734414342702651611316059DFS (%)0204060801009070503010012243648607284ZANo ZA5483No. of Events HR (95% CI) Events vs No ZA0.643 (0.46-0.91); P = .0110204060801009070503010012243648607284Gnant M, et al. ASCO 2008. Abstract LBA4.Time Since Randomization (Mos)Overall surviva

20、l, %No. of Events HR (95 % CI)ZA 16 0.595 (0.32-1.11), P = .101No ZA 26 Events vs No ZA8999048388517447355655734414342702651611316059OS8999048328467307145385554034142572411451234754No. at riskNo ZAZA0204060801009070503010Time Since Randomization (Mos)Recurrence-Free Survival (%)012243648607284No. of

21、 Events HR (95 % CI)ZA 54 0.653 (0.46-0.92), P = .014No ZA 82 Events vs No ZARFSGnant M, et al. ASCO 2008. Abstract LBA4.Direct antitumor activityImmune activationBone mets recurrenceNonbone mets recurrenceContralateralrecurrenceLocoregionalmets recurrenceDFSONONONHOHONOHHN-desmethylTAMCYP2D6Endoxif

22、enSULTs and/or UGTs?CYP3ASULTs and/or UGTs?4-hydroxyTAMCYP 206, 286, 2C9. 2C19, 3ATamoxifen (TAM)CYP3AActive metaboliteBonanni B, et al. SABCS 2007. Abstract 29.Bonanni B, et al. SABCS 2007. Abstract 29.Patients Receiving Tamoxifen, n (%)Control(n = 65)Breast Cancer(n = 20)Phenotype UM00 EM59 (80.8)

23、14 (19.2) IM5 (71.4)2 (28.6)CYP2D6 *2A genotype 1 *2A allele31 (96.9)1 (31.1) Other nonpoor allele33 (68.7)15 (31.3) PM1 (25.0)3 (75.0)CYP2C19 *17 phenotype WT + WT/*17 (EM)63 (75.0)18 (25.0) 17/*17 (UM)2 (50.0)2 (50.0)Rae JM, et al. SABCS 2007. Abstract 77.Rae JM, et al. SABCS 2007. Abstract 77.020

24、406080100Patients Remaining on Treatment (%) 10093.390.389.2PM86.0IMIM/EMEM/UMEMn =10157250120Postmenopausal women with locally advanced (T2,3,4b, N0, M0), ER-positive breast cancer(N = 211)High-Dose Fulvestrant500 mg/month + 500 mg on Day 14 of Month 1(n = 109)Week 4Week 16 (surgery)Standard-Dose F

25、ulvestrant250 mg/month (n = 102)Kuter I, et al. SABCS 2007. Abstract 23.Reduction in Ki67 Labeling Index at 4 WeeksHigh-DoseFulvestrant (n = 60)Standard-DoseFulvestrant (n = 63)P ValueMean % reduction from baseline, % (95% CI)78.8 (70.8 to 84.6)47.3 (47.3 to 61.2) .0001Absolute reduction from baseli

26、ne (95% CI)-17.5 (-15.7 to -18.8)-10.5 (-6.3 to -13.6) .0001Kuter I, et al. SABCS 2007. Abstract 23.Kuter I, et al. SABCS 2007. Abstract 23.Fulvestrant 250 mg (n = 69)Fulvestrant 500 mg (n = 69)020406080100Response to Treatment (%) 30.48836.258.011.6ORR (CR + PR*)SDOR: 1.30 (0.64-2.64)53.610.1PD*PR

27、defined as 65% reduction in tumor volume.Everolimus 10 mg/day + Letrozole 2.5 mg/day (n = 138)Placebo +Letrozole 2.5 mg/day (n = 132)Postmenopausal women with ER-positive invasive breast cancer2(N = 270)SurgeryWeek 161. Awaada A, et al. Eur J Cancer. Nov 24;Epub ahead of print.2. Baselga J, et al. S

28、ABCS 2007. Abstract 2066.UnavailableBaselga J, et al. SABCS 2007. Abstract 2066.Everolimus (n = 138)Placebo (n = 69)020406080100Response to Treatment (%) 1388CRPRNo ChangePDORR955502530410326859Baselga J, et al. SABCS 2007. Abstract 2066.Most Common Adverse Events, n (%)Everolimus Arm(n = 137)Placeb

29、o Arm(n = 132)Stomatitis50 (36.5)8 (6.1)Rash28 (20.4)10 (7.6)Thrombocytopenia25 (18.2)1 (0.8)Asthenia24 (17.5)13 (9.8)Hypercholesterolemia22 (16.1)8 (6.1)Hyperglycemia18 (13.1)4 (3.0)Pruritus18 (13.1)0Fatigue17 (12.4)6 (4.5)Anorexia17 (12.4)5 (3.8)ALT increase16 (11.7)5 (3.8)Grade 3 adverse events i

30、n everolimus arms: hyperglycemia (5.1%), stomatitis (2.2%), infections (2.2%), interstitial lung disease (2.2%), fatigue (1.5%), thrombocytopenia (1.5%), hypokalemia (1.5%), ALT increase (1.5%)1 grade 4 infection in everolimus arm 1. Fisher B, et al. J Natl Cancer Inst. 2001;93:684-690. 2. Peto R, et al. SABCS 2007. Abstract 48.Singh S, et al. SABCS 2007. Abstract 28. Mean Change in BMD for lumbar spine at 1 Year (%)-6-4-20246STRATUM-INormal BMDNo